The perinatal cardiopulmonary transition at high altitude differs from that at sea level because oxygen plays a fundamental role in the developmental changes from fetus to newborn infant. Under conditions of high altitude hypoxia, arterial oxygen saturations are lower, breathing patterns and maturation of respiratory control reflexes differ, and regression of fetal characteristics of the pulmonary vasculature proceeds more slowly. Several aspects of transition vary not only with postnatal age and altitude, but also with population group, suggesting an effect of genetic adaptation on perinatal physiology. Exposure to chronic high altitude hypoxia during the perinatal transition also results in apparent lifelong alterations in respiratory reflex responses and pulmonary vasoreactivity. Disruption of the normal process of cardiopulmonary transition can result in symptomatic high altitude pulmonary hypertension. The exaggerated hypoxemia associated with acute respiratory infections in young infants still undergoing transition contributes to infant mortality at high altitude.